WO2024127361A1 - Nanocristaux d'enzalutamide, méthodes et compositions - Google Patents

Nanocristaux d'enzalutamide, méthodes et compositions Download PDF

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WO2024127361A1
WO2024127361A1 PCT/IB2023/062806 IB2023062806W WO2024127361A1 WO 2024127361 A1 WO2024127361 A1 WO 2024127361A1 IB 2023062806 W IB2023062806 W IB 2023062806W WO 2024127361 A1 WO2024127361 A1 WO 2024127361A1
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composition
enzalutamide
nanocrystals
stabilizer
particle size
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Inventor
Flavia Chiva CARVALHO
Fernanda Isadora BONI
Denise ZARDI
Renato FARO
Gabriela BIZ
Louise L. TUNDISI
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Ferring BV
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Ferring BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • Described herein are processes for preparing nanocrystals of enzalutamide, compositions comprising them, including oral pharmaceutical compositions, and therapeutic methods using them.
  • compositions comprising nanocrystals of enzalutamide, wherein the enzalutamide nanocrystals have an average particle size diameter of ⁇ 250 nm.
  • the enzalutamide nanocrystals may have an average particle size diameter of 180 nm to 220 nm.
  • the enzalutamide nanocrystals may have a poly dispersity index of from 0.05 to 0.30, as measured by dynamic light scattering.
  • the enzalutamide nanocrystals may have a polydispersity index of ⁇ 0.20, as measured by dynamic light scattering.
  • the average particle size of the nanocrystals in the composition may not vary by more than ⁇ 10% after storage at room temperature for 40 days.
  • the composition is stable against sedimentation of enzalutamide after storage at room temperature for 3 months.
  • the composition further comprises water.
  • the composition may be in the form of an aqueous suspension comprising the enzalutamide nanoparticles suspended in an aqueous carrier.
  • lyophilized compositions prepared from a composition in accordance with any of the foregoing embodiments, optionally further comprising a lyophilization stabilizer.
  • compositions prepared from a composition in accordance with any of the foregoing embodiments, optionally further comprising a granulation excipient.
  • any composition as described herein does not include hydroxypropyl methyl cellulose (HPMC).
  • the one or more low viscosity water-soluble polymeric stabilizers comprises one or more selected from polyvinyl alcohol, polyvinylpyrrolidone having an average molecular weight of 60,000 Daltons or greater, hydroxypropyl methylcellulose having an average molecular weight of 40,000 to 100,000 Daltons, and hydroxypropyl methylcellulose having an average molecular weight of 10000 to 60000 Daltons.
  • the one or more low viscosity water-soluble polymeric stabilizers comprises polyvinyl alcohol.
  • the aqueous dispersion may further comprise one or more non-ionic stabilizers.
  • the one or more non-ionic stabilizers may comprise one or more selected from polyethylene glycol sorbitan monooleate, block copolymers of polyethylene oxide and polypropylene oxide, a-tocopherol, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene nonylphenol ethers, and polyoxyethylene 15 hydroxy stearate.
  • the non-ionic stabilizer comprises polyvinyl alcohol and polyethylene glycol sorbitan monooleate.
  • the wet-milling may be conducted in a grinding chamber containing grinding beads in an amount of 50% w/w to 75% w/w, based on the capacity of the grinding chamber.
  • the wet-milling may be conducted with grinding beads having a diameter of from about 0.1 mm to about 0.4 mm.
  • the wet-milling may be conducted with grinding beads having a diameter of from about 0.1 mm to about 0.2 mm.
  • the wet-milling may be conducted at temperature from about 4°C to 15 °C.
  • the wet-milling may be conducted at temperature from about 5°C to 10 °C.
  • the wet-milling may be conducted at a speed of from about 1000 rpm to about 2500 rpm.
  • the enzalutamide may have an average particle size diameter of > 100000 nm prior to the wet-milling.
  • the enzalutamide may have an average particle size diameter on the order of 10000 nm prior to the wet-milling.
  • the enzalutamide nanocrystals may have an average particle size diameter of from 180 nm to 220 nm.
  • enzalutamide nanocrystals prepared by a process according to any embodiments disclosed herein, wherein the enzalutamide nanocrystals have an average particle size diameter of ⁇ 250 nm.
  • the nanocrystals may have an average particle size diameter of 180 nm to 220 nm.
  • the enzalutamide nanocrystals may have a poly dispersity index of from 0.05 to 0.30, as measured by dynamic light scattering.
  • the enzalutamide nanocrystals may have a poly dispersity index of ⁇ 0.20, as measured by dynamic light scattering.
  • the enzalutamide nanocrystals may have a saturation solubility in water at 37 ° that is about 20-fold that of nonnanosized enzalutamide having an average particle size of about 6,000 nm, when assessed 4 hours after being dissolved in water.
  • the enzalutamide nanocrystals may have a saturation solubility in water at 37 ° that is about twice that of non-nanosized enzalutamide having an average particle size of about 6,000 nm, when assessed 8 hours after being dissolved in water.
  • the process may further comprise preparing the enzalutamide nanocrystals by wet-milling enzalutamide with an aqueous dispersion comprising a low viscosity water-soluble polymeric stabilizer (e.g., in accordance with any embodiments disclosed herein).
  • the process may further comprise formulating the aqueous composition as an oral liquid pharmaceutical composition.
  • the process may further comprise drying the aqueous composition to obtain a dried composition. Drying the composition may comprise lyophilizing the composition, granulating the composition, or spray-drying the composition.
  • the process may further comprise formulating the dried composition as a dry oral pharmaceutical composition.
  • oral pharmaceutical compositions prepared by a process according to any embodiments disclosed herein, and oral pharmaceutical compositions comprising a composition according to any embodiments disclosed herein.
  • An oral pharmaceutical composition may further comprise a penetration enhancer.
  • the oral pharmaceutical composition does not include hydroxypropyl methyl cellulose (HPMC).
  • HPMC hydroxypropyl methyl cellulose
  • the oral pharmaceutical composition may be packaged to provide a daily dose of 50 mg to 160 mg enzalutamide, optionally to provide a daily dose of 50 mg to less than 160 mg enzalutamide.
  • Also provided are methods of administering enzalutamide comprising orally administering a composition according to any embodiments described herein, or an oral pharmaceutical composition according to any embodiments described herein, to a subject in need thereof, optionally wherein the composition is administered at a daily dose of 50 mg to 160 mg enzalutamide, further optionally wherein the composition is administered at a daily dose of 50 mg to less than 160 mg enzalutamide.
  • compositions and oral pharmaceutical compositions according to any embodiments described herein, for use in treating prostate cancer optionally wherein the use comprises administering the composition at a daily dose of 50 mg to 160 mg enzalutamide, further optionally wherein the use comprises administering the composition at a daily dose of 50 mg to less than 160 mg enzalutamide.
  • compositions and oral pharmaceutical compositions according to any embodiments described herein, in the manufacture of a medicament for treating prostate cancer, optionally wherein the medicament comprises a daily dose of 50 mg to 160 mg enzalutamide, further optionally wherein the medicament comprises a daily dose of 50 mg to less than 160 mg enzalutamide.
  • FIG. 1 illustrates a process for preparing enzalutamide nanocrystals as described herein, according to a specific implementation.
  • FIG. 2 illustrates a size distribution profile for enzalutamide nanocrystals prepared as described herein from different wet-milling formulations.
  • FIG. 3 presents physical stability data of enzalutamide compositions described herein.
  • FIG. 4 is a comparative profile of enzalutamide saturation solubility (water, 37 °C) before and after nanonization as described herein.
  • FIG. 5A-5C illustrate results of a cytotoxicity assay of non-nanosized enzalutamide, XTANDI®, and enzalutamide nanocrystals as described herein (ENC-004).
  • the present disclosure provides processes for preparing nanocrystals of enzalutamide, compositions comprising them, including oral pharmaceutical compositions, and therapeutic methods using them.
  • the enzalutamide nanocrystals and compositions described herein offer advantages including improved intrinsic drug solubility and dissolution rate (believed to be associated with improved bioavailability) and good physical stability.
  • the enzalutamide compositions described herein may contain the same amount of enzalutamide in a smaller volume than enzalutamide compositions prepared with non-nanosized enzalutamide or solubilized enzalutamide (e.g., enzalutamide solubilized in caprylocaproyl polyoxylglycerides vehicle), and therefore provide the same dose in a smaller volume.
  • the enzalutamide nanocrystals described herein have an average particle size diameter of ⁇ 250 nm, including about 200 nm (e.g., from 180 nm to 220 nm) and are prepared by wet-milling with a stabilizer as described herein.
  • compositions described herein may be prepared as liquid or dry pharmaceutical compositions, e.g., as liquid or dry (solid) dosage forms. Exemplary processes, components of intermediate and pharmaceutical compositions, as well as specific illustrative embodiments, are discussed in more detail below.
  • a phrase in the form “A/B” or in the form “A and/or B” means (A), (B), or (A and B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).
  • the terms “comprising,” “including,” and “containing” are used expansively to mean that the described compositions, methods, or kits include at least the stated elements, and may include other elements that are not specified.
  • the phrase “consisting essentially of’ is used to include those elements specifically recited and additional elements that do not materially affect the basic and novel characteristics of the claimed invention, such as ingredients that do not materially undermine the solubility of the enzalutamide.
  • subject denotes any mammal, including humans.
  • a subject may be suffering from or at risk of developing a condition that can be treated or prevented with an androgen receptor antagonist, such as enzalutamide, or may be taking androgen receptor antagonist for other purposes.
  • an androgen receptor antagonist such as enzalutamide
  • administer refers to providing, giving, dosing and/or prescribing, such as by a health professional or his or her authorized agent or under his or her direction, and putting into, taking, or consuming, such as by a health professional or the subject.
  • treat include alleviating, abating or ameliorating a disease or condition or one or more symptoms thereof, whether or not the disease or condition is considered to be “cured” or “healed,” and whether or not all symptoms are resolved.
  • the phrases “therapeutically effective amount” and “therapeutically effective dose” refer to an amount or dose that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the targeted condition, even though such amount or dose is deemed to be a therapeutically effective amount or dose by those of skill in the art. For convenience only, exemplary doses and therapeutically effective amounts are provided below with reference to adult human subjects. Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and/or condition/disease. Enzalutamide
  • compositions described herein comprise enzalutamide.
  • the enzalutamide is formulated in nanocrystal form, as discussed in more detail below. While not wanting to be bound by theory, it is believed that formulating the enzalutamide in nanocrystal form may improve solubility, stability, and bioavailability.
  • the nanoscale size may enhance the dissolution rate and increase the saturation solubility (e.g., achieve in vivo saturation without precipitation).
  • the nanocrystal form may improve bioavailability and/or in vivo performance of a composition as described herein.
  • the enzalutamide compositions described herein may contain the same amount of enzalutamide in a smaller volume than enzalutamide compositions prepared with non-nanosized or solubilized enzalutamide, and therefore provide the same dose in a smaller volume.
  • Enzalutamide has the chemical name 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzamide, the molecular formula C21H16F4N4O2S, and a molecular weight of 464.44. It is registered under CAS Registry Number 915087-33-1.
  • the structural formula of enzalutamide is set forth below:
  • Enzalutamide compositions have been described in previous patents and patent applications, for example, in WO 2015/118015, US 2020/0397756, and CN108815129. However, as explained herein, there remains a need for enzalutamide pharmaceutical compositions (e.g., oral enzalutamide pharmaceutical compositions) with desirable properties, as well as processes for preparing them.
  • the enzalutamide nanocrystals described herein have an average particle size ⁇ 250 nm, including an average particle size of about 200 nm, or less, such as an average particle size of from 180 nm to 220 nm. Thus, the nanocrystals may have an average particle size of about 200 nm, about 195 nm, about 180 nm, or less. Average particle size can be measured by processes known in the art, such as by dynamic light scattering (DLS).
  • DLS dynamic light scattering
  • the nanocrystals have a low polydispersity index, indicative of a uniform particle size distribution.
  • the nanocrystals have a polydispersity index of from about 0.05 to about 0.30 (e.g., from about 5% to about 30%), including from about 0.1 to 0.3 (e.g., 10% to 30%).
  • Polydispersity can be measured by processes known in the art, such as by dynamic light scattering (DLS).
  • enzalutamide nanocrystals are prepared and/or used that have an average particle size of ⁇ 250 nm, including about 200 nm or less, such as from 180 nm to 200 nm. Additionally or alternatively, the enzalutamide nanocrystals have a low polydispersity index, such as a poly dispersity index of from about 0.1 to 0.3.
  • compositions described herein may comprise enzalutamide nanocrystals in any suitable amount.
  • the compositions described herein may comprise enzalutamide nanocrystals in any amount suitable for providing a therapeutically effective dose in a suitable amount of pharmaceutical composition for oral administration.
  • a pharmaceutical composition as described herein includes oral liquid pharmaceutical compositions (e.g., in bulk form, in stick packs, or filled into capsules, such as a soft or hard gelatin capsule) and oral dry pharmaceutical compositions (e.g., in powder, granule or tablet form, optionally provided in a stick pack, sachet or capsule, such as a hard gelatin capsule).
  • compositions comprising enzalutamide nanocrystals as described herein may include a therapeutically effective amount (e.g., about 160 mg) of enzalutamide in a suitable amount of pharmaceutical composition for oral administration.
  • a therapeutically effective amount e.g., about 160 mg
  • an enzalutamide compositions as described herein may contain the same amount of enzalutamide in a smaller volume than enzalutamide compositions prepared with non-nanosized enzalutamide, and therefore provide the same dose in a smaller volume.
  • compositions comprising enzalutamide nanocrystals as described herein may comprise a therapeutically effective amount that is less than 160 mg enzalutamide (such as from 50 mg to less than 160 mg, including about 100 mg enzalutamide) in a suitable amount of composition for oral administration.
  • a liquid composition or oral liquid pharmaceutical compositions of enzalutamide nanocrystals as described herein may comprise from about 2.5 mg to about 150 mg of enzalutamide per 1 mL of the composition, including from about 2.5 mg to about 100 mg of enzalutamide per 1 mb of the composition, from about 2.5 mg to about 75 mg of enzalutamide per 1 mL of the composition, from about 2.5 mg to about 50 mg of enzalutamide per 1 mL of the composition, from about 2.5 mg to about 25 mg of enzalutamide per 1 mL of the composition, or from about 2.5 mg to about 7.5 mg of enzalutamide per 1 mL of the composition, such as from 2.5 mg to 150 mg of enzalutamide per 1 mL of the composition, from 2.5 mg to 100 mg of enzalutamide per 1 mL of the composition, from 2.5 mg to 75 mg of enzalutamide per 1 mL of the composition, from 2.5 mg to 50 mg of enzalutamid
  • a dry composition or oral dry pharmaceutical compositions of enzalutamide nanocrystals as described herein may comprise from about 32 mg to about 320 mg of enzalutamide per g of the composition, from about 32 mg to about 50 mg of enzalutamide per g of the composition, from about 32 mg to about 75 mg of enzalutamide per g of the composition, from about 32 to about 100 mg of enzalutamide per g of the composition, from about 32 to about 160 mg of enzalutamide per g of the composition, from about 32 to about 180 mg of enzalutamide per g of the composition, from about 32 to about 225 mg of enzalutamide per g of the composition, or from about 32 to about 280 mg of enzalutamide per g of the composition, such as from 32 mg to 320 mg of enzalutamide per g of the composition, from 32 mg to 50 mg of enzalutamide per g of the composition, from 32 mg to
  • an oral pharmaceutical composition of enzalutamide nanocrystals may be prepared by first preparing an aqueous composition comprising (i) enzalutamide nanocrystals; and (ii) a stabilizer; and (iii) optionally, one or more additional pharmaceutically acceptable ingredients, including, optionally, a permeation enhancer.
  • a composition may be prepared using pre-formed enzalutamide nanocrystals or may result from a process of preparing enzalutamide nanocrystals as described herein.
  • the aqueous composition comprising (i) enzalutamide nanocrystals and (ii) a stabilizer as described herein is referred to herein below from time to time as an “intermediate” composition, although it may be suitable for administration as an oral liquid pharmaceutical composition, as also discussed in more detail below.
  • An oral liquid pharmaceutical composition may be prepared by formulating the aqueous composition (e.g. the “intermediate” composition) as an oral liquid pharmaceutical composition, including optionally adding one or more pharmaceutically acceptable components, such as one or more selected from preservatives, antioxidants, stabilizers, thickeners, etc.
  • a dry oral pharmaceutical composition may be prepared by a process comprising drying the aqueous composition (e.g.
  • the “intermediate” composition to obtain a dried composition and formulating the dried composition as a dry (e.g., solid) oral pharmaceutical dosage form.
  • the amount of enzalutamide in the aqueous composition is not particularly limited, because the aqueous composition can be diluted or concentrated (or dried) to obtain a pharmaceutical composition that comprises a therapeutically effective dose in a suitable amount for oral administration. Exemplary amounts are provided in the discussion that follows for illustration purposes.
  • processes for preparing enzalutamide nanocrystals by wet-milling enzalutamide to obtain nanocrystals comprise wetmilling enzalutamide with an aqueous dispersion comprising a stabilizer (e.g. one or more low viscosity water-soluble polymeric stabilizers) to obtain nanocrystals of enzalutamide.
  • a stabilizer e.g. one or more low viscosity water-soluble polymeric stabilizers
  • the processes described herein can be used to obtain enzalutamide nanocrystals having an average particle size diameter of ⁇ 250 nm.
  • low viscosity water-soluble polymeric stabilizers refers to a viscosity in the range of 2.0 to 6.0 mPa.s-1 when prepared at a concentration of 40g/L.
  • the one or more low viscosity water-soluble polymeric stabilizers may comprise one or more selected from polyvinyl alcohol, polyvinylpyrrolidone having an average molecular weight of 60,000 Daltons or greater, hydroxypropyl methylcellulose having an average molecular weight of 40,000 to 100,000 Daltons, and hydroxypropyl methylcellulose having an average molecular weight of 10,000 to 60,000 Daltons.
  • a composition as described herein does not include hydroxypropyl methyl cellulose (HPMC).
  • HPMC hydroxypropyl methyl cellulose
  • suitable polyvinyl alcohol (PVA) stabilizers include PVA 4-88, PVA 4-99, PVA 5-88 and PVA 5-99, where the first number indicates viscosity (e.g., of 4-6 mPa.s-1) and the second number indicates degree of alcoholysis (e.g., 86-90 %).
  • suitable polyvinylpyrrolidone (PVP) stabilizers include PVP having an average molecular weight in a range from 8,000 to 60,000 Daltons, including PVP K-12, PVP K-15, and PVP K-30.
  • a suitable PVP stabilizer has an average molecular weight of 60,000 Daltons or greater, such as PVP K-30.
  • suitable hydroxypropyl methylcellulose stabilizers include hydroxypropyl methylcellulose having an average molecular weight of 40,000 to 100,000 Daltons, and hydroxypropyl methylcellulose having an average molecular weight of 10,000 to 60,000 Daltons.
  • the low viscosity water-soluble polymeric stabilizer comprises polyvinyl alcohol, such as PVA 4-88.
  • the low viscosity water-soluble polymeric stabilizer(s) may be used in any suitable amount, such as from 1% w/w to 10% w/w of an aqueous milling composition that also comprises the enzalutamide (and optionally, one or more non-ionic stabilizers), as discussed in more detail below.
  • the aqueous dispersion further comprises one or more non-ionic stabilizers.
  • the one or more non-ionic stabilizers may comprise one or more selected from polyethylene glycol sorbitan monooleate (polysorbate 80), block copolymers of polyethylene oxide and polypropylene oxide (e.g., Poloxamer 124, Poloxamer 188, Poloxamer 407), a- tocopherol, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene nonylphenol ethers, and polyoxyethylene 15 hydroxy stearate.
  • the non- ionic stabilizer comprises polyethylene glycol sorbitan monooleate (polysorbate 80).
  • the non- ionic stabilizer(s) may be used in any suitable amount, such as from 0% w/w to 2% w/w of an aqueous milling composition that also comprises the enzalutamide and low viscosity water-soluble polymeric stabilizer(s), as discussed in more detail below.
  • the wet-milling may be conducted under any suitable conditions for obtaining enzalutamide nanocrystals having an average particle size diameter of ⁇ 250 nm. It was determined that the enzalutamide concentration and stabilizer present in the wet-milling composition, milling time and milling speed impact the average particle size diameter of the obtained nanocrystals. For example, the higher the concentration of enzalutamide, the shorter the milling time required to obtain nanocrystals with an average particle size diameter of less than 250 nm. Also, higher milling speed was associated with smaller particle size. It also was found that enzalutamide concentration, milling time, and milling speed impact the polydispersity index (PDI) of the obtained nanocrystals. For example, higher concentrations of enzalutamide were associated with lower PDI values.
  • PDI polydispersity index
  • the wet-milling is conducted using a dual centrifuge device, such as the DeltaVita® 1 manufactured by Netzsch, or a similar device with larger capacity.
  • the wet-milling is conducted in a grinding chamber containing grinding beads in an amount of 50% w/w to 75% w/w, based on the capacity of the grinding chamber.
  • the wet-milling is conducted with grinding beads having a diameter of from about 0.1 mm to about 0.4 mm, including from 0.1 mm to 0.4 mm, such as from about 0.1 mm to about 0.2 mm, including from 0.1 mm to 0.2 mm.
  • the wet-milling is conducted at a speed of from about 1000 rpm to about 2500 rpm, including a speed from 1000 rpm to 2500 rpm, or any value therebetween.
  • the wet-milling may be conducted for a time effective for obtaining enzalutamide nanocrystals having an average particle size diameter of ⁇ 250 nm.
  • the grinding time of the wet-milling process is from about 60 minutes to about 300 minutes, including 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, or any value therebetween.
  • the wet-milling may be conducted at a temperature selected to preserve or promote stability of the enzalutamide.
  • the wet-milling is conducted at a temperature from about 4°C to about 15 °C, such as a temperature from 4°C to 15 °C, including a temperature from about 5°C to about 10 °C, such as a temperature from 5°C to 10 °C.
  • the particle size of enzalutamide starting material is not particularly limited.
  • the enzalutamide has an average particle size diameter of > 100000 nm prior to the wet-milling. In some embodiments, the enzalutamide has an average particle size diameter on the order to 10000 nm prior to the wet-milling.
  • processes as described herein can be used to obtain enzalutamide nanocrystals having an average particle size diameter of ⁇ 250 nm, including from about 180 nm to about 220 nm, or smaller, such as about 200 nm, about 195 nm, about 190 nm, about 185 nm, about 180 nm, or smaller.
  • average particle size diameter of the nanocrystals may be determined by dynamic light scattering (DLS).
  • nanocrystals prepared by a process as described herein may have a low polydispersity index, indicative of a uniform particle size distribution.
  • the nanocrystals have a polydispersity index of from about 0.05 to about 0.30, including from about 0.1 to 0.3.
  • the poly dispersity index of the nanocrystals may be determined by dynamic light scattering (DLS).
  • FIG. 1 illustrates a process of preparing enzalutamide nanocrystals as described herein.
  • grinding beads e.g., zirconium beads
  • a wet-milling apparatus e.g., the DeltaVita® 1 manufactured by Netzsch, or similar device with larger capacity
  • the aqueous dispersion comprising the low viscosity water-soluble polymeric stabilizer(s) (and optionally further comprising the non-ionic stabilizers) is prepared at a concentration of from about 2% w/w to about 10% w/w and added to the grinding chamber in an amount of about 30 % w/w to about 45 % w/w of the capacity of the grinding chamber.
  • the enzalutamide starting material is added to the grinding chamber in an amount of about 5% w/w to about 15% w/w of the capacity of the grinding chamber.
  • Wet-milling is conducted at 1000 to 2500 rpm for 60 to 300 minutes at a temperature of from 4°C to 10 °C.
  • the aqueous composition may be recovered from the grinding beads by any suitable method, such as filtration, aspiration, etc.
  • a process as described herein results in an aqueous composition comprising the enzalutamide nanocrystals and stabilizer(s), e.g., an aqueous dispersion of the enzalutamide nanocrystals and stabilizer(s).
  • a composition is referred to herein from time to time as an “intermediate” composition.
  • enzalutamide nanoparticles as described herein may be prepared using an aqueous milling composition comprising a stabilizer, and intermediate and pharmaceutical compositions as described herein may comprise a stabilizer. While not wanting to be bound by theory, it is believed that the stabilizer may stabilize the dispersion of nanocrystals (e.g., enzalutamide nanocrystals) in the aqueous vehicle.
  • nanocrystals e.g., enzalutamide nanocrystals
  • the stabilizer may be one or more selected from low viscosity water-soluble polymeric stabilizers and non-ionic stabilizers.
  • low viscosity refers to a viscosity in the range of 2.0 to 6.0 mPa.s-1 when prepared at a concentration of 40g/L.
  • suitable low viscosity water-soluble polymeric stabilizers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
  • suitable polyvinyl alcohol (PVA) stabilizers include PVA 4-88, PVA 4-99, PVA 5- 88 and PVA -99, where the first number indicates viscosity (e.g., of 4-6 mPa.s-1) and the second number indicates degree of alcoholysis (e.g., 86-90%).
  • suitable polyvinylpyrrolidone (PVP) stabilizers include PVP having an average molecular weight in a range from 8000 to 60,000 Daltons, including PVP K-12, PVP K-15, and PVP K-30. In some embodiments, a suitable PVP stabilizer has an average molecular weight of 60,000 Daltons or greater, such as PVP K-30.
  • suitable hydroxypropyl methylcellulose stabilizers include hydroxypropyl methylcellulose having an average molecular weight of 40,000 to 100,000 Daltons, and hydroxypropyl methylcellulose having an average molecular weight of 10,000 to 60,000 Daltons.
  • “low viscosity” means having a viscosity in the range of 2.0 to 6.0 mPa.s-1 at a concentration of 40g/L.
  • non-ionic stabilizers include, but are not limited to, polyethylene glycol sorbitan monooleate (polysorbate 80), block copolymers of polyethylene oxide and polypropylene oxide (e.g., Poloxamer 124, Poloxamer 188, Poloxamer 407), a-tocopherol, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene nonylphenol ethers, and polyoxyethylene 15 hydroxy stearate.
  • polyethylene glycol sorbitan monooleate polysorbate 80
  • block copolymers of polyethylene oxide and polypropylene oxide e.g., Poloxamer 124, Poloxamer 188, Poloxamer 407
  • a-tocopherol polyoxyethylene alkyl ethers
  • polyoxyethylene castor oil derivatives polyoxyethylene nonylphenol ethers
  • polyoxyethylene 15 hydroxy stearate polyoxyethylene 15 hydroxy stearate
  • a composition as described herein comprises polyvinyl alcohol and polyethylene glycol sorbitan monooleate.
  • an aqueous composition as described herein e.g., a milling composition, intermediate composition, or pharmaceutical composition
  • a total stabilizer content of from about 1% to about 15% w/w, including from about 1% to about 10% w/w, including from 1% to 10% w/w, such as from about 2% to about 5% w/w, including from 2% to 5% w/w, including about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w, such as 2% w/w,
  • compositions as described herein that includes more than one stabilizer may comprise a relatively large amount of one and a relatively small amount of the other(s), or may comprise relatively equal amounts of each.
  • the stabilizer may be or comprise polyvinyl alcohol.
  • an aqueous composition as described herein e.g., a milling composition, intermediate composition, or pharmaceutical composition
  • the stabilizer may be or comprise polyvinylpyrrolidone, such as PVP having an average molecular weight of 60,000 Daltons or greater, such as PVP K-30.
  • an aqueous composition as described herein e.g., a milling composition, intermediate composition, or pharmaceutical composition
  • the stabilizer may be or comprise polyethylene glycol sorbitan monooleate (e.g., polysorbate 80).
  • an aqueous composition as described herein e.g., a milling composition, intermediate composition, or pharmaceutical composition
  • a composition as described herein may comprise one or more other components suitable for an intermediate of a pharmaceutical composition, or suitable for an oral pharmaceutical composition formulated as a liquid or dry (solid) composition.
  • a composition as described herein optionally may further comprise one or more pharmaceutically acceptable excipients such as viscosity adjusting agents (e.g., thickeners), diluents, pH adjusting agents, colorants, flavoring agents, taste-masking agents, preservatives, etc.
  • a composition as described herein further comprises a permeation enhancer.
  • an aqueous composition as described herein may be subjected to a drying process (such as lyophilization) to obtain a dry (solid) composition, which can be formulated as a dry (e.g., solid) oral pharmaceutical composition.
  • a drying process such as lyophilization
  • the composition may comprise a lyophilization excipient.
  • the lyophilization excipient may be any compound suitable for use in oral pharmaceutical compositions that may protect the nanocrystals during the lyophilization process, such as any cryoprotectant or lyoprotectant suitable for use in oral pharmaceutical compositions.
  • a lyophilization excipient may be used in any suitable amount effective to protect the nanocrystals during the lyophilization process, such as from about 0.1% w/w to about 50% w/w, including from 0.1% to 50% w/w, based on the weight of the aqueous composition before drying.
  • an aqueous composition as described herein may be subjected to a granulation process (such as wet granulation) to obtain a dry (solid) composition, which can be formulated as a dry (e.g., solid) oral pharmaceutical composition.
  • a granulation process such as wet granulation
  • the composition may comprise a wet granulation excipient.
  • the wet granulation excipient may be any compound suitable for use in oral pharmaceutical compositions that facilitates granulation, such as one or more selected from disintegrants (e.g., povidone, crospovidone, corn starch, etc.) wetting agents (polaxamers, carboxymethylcellulose, etc.), binders (povidone, corn starch, hydroxy ethylmethyl cellulose, hypromellose, lactose monohydrate, etc.), glidants (glyceryl monoestearate, talc, etc.), and diluents (microcrystalline cellulose, corn starch, lactose monohydrate, etc.).
  • disintegrants e.g., povidone, crospovidone, corn starch, etc.
  • wetting agents polyamers, carboxymethylcellulose, etc.
  • binders povidone, corn starch, hydroxy ethylmethyl cellulose, hypromellose, lactose monohydrate, etc.
  • a composition as described herein e.g., a pharmaceutical composition
  • the permeation enhancer may enhance the solubility of components of the composition (e.g., the enzalutamide), and/or may enhance in vivo permeation of the enzalutamide.
  • the permeation enhancer may improve (shorten) the dissolution rate of the enzalutamide in the composition.
  • the permeation enhancer may act as a paracellular junction modulator (rather than a mucolytic agent that can cause damage to the intestinal mucosa).
  • a permeation enhancer is a surfactant (e.g., an anionic surfactant).
  • the permeation enhancer may be one or more selected from sodium salts of a medium chain fatty acid, CIO - Cl 8 alcohol sulfates, bile salt derivatives (e.g.
  • fatty acid means a carboxylic acid having the formula RCOOH, where R represents an aliphatic group, such as an alkyl group, that comprises from 4 to 22 carbon atoms.
  • Fatty acids can be saturated, monounsaturated, or polyunsaturated.
  • a fatty acid can have a medium-chain length (e.g., medium chain fatty acid), wherein the fatty acids may be saturated or unsaturated.
  • medium chain fatty acid refers to a fatty acid that consists of 6 to 14 carbon atoms, such as caproic acid (C6), caprylic acid (C8), capric acid (CIO), and lauric acid (Cl 2).
  • Examples of suitable sodium salts of a medium chain fatty acid for use as a permeation enhancer include, but are not limited to, sodium caprate and sodium caprylate.
  • suitable bile salt derivatives for use as a permeation enhancer include, but are not limited to, sodium cholate, sodium taurocholate (e.g., sodium deoxycholate, sodium taurodeoxy cholate).
  • Suitable coconut oil derivatives and/or palm oil derivatives for use as a permeation enhancer include, but are not limited to, methyl ester sulfonates (MES), sodium lauryl sulfate (SLS), sodium coco sulfate (SCS), sodium laureth sulfate (SLES), cocoyl chloride), potassium cocoyl glycinate, sodium cocoyl glycinate, palmitic acid and palm kernel oil.
  • a composition as described herein may comprise one or more permeation enhancers selected from sodium caprate, sodium caprylate, sodium cholate, sodium deoxycholate, and sodium lauryl sulfate.
  • a composition as described herein may comprise one permeation enhancer compound, or a combination of permeation enhancers, such as a combination of any two or more of the permeation enhancers listed above.
  • the permeation enhancers(s) can be present in any suitable amount, such as any amount effective to achieve the desired impact on solubility and/or permeation. When combinations of permeation enhancers are used, they each may be present in any suitable amount.
  • a composition as described herein that includes more than one permeation enhancer may comprise a relatively large amount of one and a relatively small amount of the other(s), or may comprise relatively equal amounts of each.
  • the permeation enhancer is or comprises sodium caprate.
  • a composition as described herein has a sodium caprate content of from about 0.25% w/w to about 50% w/w, including about 0.25% w/w, about 0.5% w/w, about 1% w/w, about 5 % w/w, about 10 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 40 % w/w, or about 50 % w/w, relative to the amount of enzalutamide, or any value therebetween.
  • the permeation enhancer is or comprises sodium caprylate.
  • a composition as described herein has a sodium caprylate content of from about 1% w/w to about 50% w/w, including about 1% w/w, about 5 % w/w, about 10 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 40 % w/w, or about 50 % w/w, relative to the amount of enzalutamide, or any value therebetween.
  • the permeation enhancer is or comprises sodium cholate (e.g., sodium deoxycholate).
  • a composition as described herein has a sodium cholate (e.g., sodium deoxy cholate) content of from about 0.25% w/w to about 10% w/w, including about 0.25% w/w, 0.5% w/w, 0.25% w/w, about 1 % w/w, about 2 % w/w, about 3 % w/w, about 4 % w/w, about 5 % w/w, or about 6 % w/w, about 7 % w/w, about 8 % w/w, about 9 % w/w, or about 10 % w/w, relative to the amount of enzalutamide, or any value therebetween.
  • the permeation enhancer is or comprises sodium lauryl sulfate.
  • a composition as described herein has a sodium lauryl sulfate content of about 1% w/w to about 50% w/w, including about 1% w/w, about 5 % w/w, about 10 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 40 % w/w, or about 50 % w/w, relative to the amount of enzalutamide, or any value therebetween.
  • Antioxidants are examples of about 1% w/w to about 50% w/w, including about 1% w/w, about 5 % w/w, about 10 % w/w, about 20 % w/w, about 25 % w/w, about 30 % w/w, about 40 % w/w, or about 50 % w/w, relative to the amount of enzalutamid
  • compositions described herein may comprise one or more antioxidants.
  • suitable antioxidants include butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), ascorbic palmitate, sodium metabisulfite, sodium thiosulfate, propyl gallate, gamma linoleic acid, ascorbic acid, ethylenediaminetetraacetic acid (EDTA), alpha tocopherol, and DL-methionine.
  • BHA butylated hydroxy anisole
  • BHT butylated hydroxy toluene
  • EDTA ethylenediaminetetraacetic acid
  • a composition as described herein may comprise an antioxidant.
  • a composition as described herein may comprise one or both of BHA and BHT.
  • the anti oxi dant(s) may be present in any suitable amount, such as from 0.001% to about 10% w/w of the composition.
  • a composition as described herein may comprise one or more of sweetening agent(s) and/or one or more flavoring agent(s).
  • suitable sweetening agents include, but are not limited to, sucralose, glycyrrhizic acid and its salts (e.g., ammonium glycyrrhizinate), saccharin, aspartame, acesulfame potassium, cyclamate, erythritol, and neotame.
  • a composition as described herein may comprise a sweetening agent.
  • a composition as described herein may comprise one or more sweetening agent(s) selected from sucralose and ammonium glycyrrhizinate. The sweetening agent(s) may be present in any suitable amount.
  • Suitable flavoring agents include, but are not limited to, vanilla flavor, banana flavor, grapefruit flavor, strawberry flavor, raspberry flavor, bubble gum flavor, and caramel flavor.
  • a composition as described herein may comprise a flavoring agent.
  • a composition as described herein may comprise vanilla flavor.
  • the flavoring agent(s) may be present in any suitable amount.
  • compositions described herein As noted above, in specific embodiments of any of the composition embodiments described herein (e.g., a milling composition, an intermediate composition, a pharmaceutical composition), the enzalutamide nanocrystals are obtained by a process as described herein. Except where expressly described as a dry composition, the compositions described herein (e.g., a milling composition, an intermediate composition, a pharmaceutical composition), may further comprise water.
  • aqueous compositions e.g., milling compositions, intermediate compositions, or pharmaceutical compositions
  • aqueous compositions comprising:
  • a polymeric stabilizer comprising one or more low viscosity water-soluble polymers (e.g., polyvinyl alcohol), and
  • a non-ionic stabilizer e.g., polyethylene glycol sorbitan monooleate
  • the aqueous composition comprises:
  • the aqueous composition may be an aqueous dispersion comprising the enzalutamide nanocrystals dispersed in an aqueous vehicle.
  • the aqueous composition may be an intermediate formulation that is subject to further processing to obtain a pharmaceutical composition.
  • an aqueous composition as described above may be subjected to further processing to formulate the aqueous composition as an oral liquid pharmaceutical composition.
  • Such further processing may include one or more of adjusting the concentration of the solution and adding one or more pharmaceutically acceptable components.
  • an aqueous composition as described above may not require further processing to be suitable for use as an oral liquid pharmaceutical composition; that is an aqueous composition as described above may be an oral liquid pharmaceutical composition.
  • an aqueous composition as described above is subjected to further processing to formulate the aqueous composition as a dry oral pharmaceutical composition.
  • an aqueous composition as described above may be subjected to a drying process (such as granulation and/or lyophilization and/or spray drying) to obtain a dry (solid) composition.
  • a dried composition is formulated into a dry oral pharmaceutical composition for administration.
  • a dry oral pharmaceutical composition may comprise a lyophilization excipient.
  • a dry oral pharmaceutical composition may comprise a granulation excipient.
  • compositions for the oral administration of enzalutamide.
  • compositions prepared by a process described herein typically include (i) enzalutamide nanocrystals and (ii) a stabilizer, initially prepared in an aqueous vehicle, e.g., as a result of the nanosizing process or prepared from preformed nanocrystals.
  • a stabilizer initially prepared in an aqueous vehicle, e.g., as a result of the nanosizing process or prepared from preformed nanocrystals.
  • the preparation of enzalutamide nanocrystals as described herein results in an aqueous composition comprising the enzalutamide nanocrystals and stabilizer, in an aqueous vehicle (e.g., water)
  • an aqueous vehicle e.g., water
  • the resulting aqueous composition may be a dispersion of enzalutamide nanocrystals nanocrystals dispersed in an aqueous solvent.
  • the aqueous composition resulting from the nanosizing process is suitable for use as an oral liquid pharmaceutical composition.
  • an aqueous composition as herein may be packaged in a bulk package (e.g., a bottle), in a unit dose package (e.g., unit dose bottles, vials or pouches) or filled into capsules.
  • the aqueous composition is formulated to obtain an oral liquid pharmaceutical composition.
  • an enhancer and/or one or more other pharmaceutically acceptable components may be added to obtain an oral liquid pharmaceutical composition.
  • An oral liquid pharmaceutical composition as described herein may be packaged in a bulk package (e.g., a bottle), in a unit dose package (e.g., unit dose bottles, vials or pouches) or filled into capsules.
  • the aqueous composition is dried to obtain a dry (solid) composition that may be formulated as a dry oral pharmaceutical composition.
  • a dry (solid) composition that may be formulated as a dry oral pharmaceutical composition.
  • an aqueous composition as described above may be subject to a drying step, such as a granulation and/or lyophilization step and/or spray drying step, to obtain a dried composition (e.g., a solid composition).
  • a drying step such as a granulation and/or lyophilization step and/or spray drying step, to obtain a dried composition (e.g., a solid composition).
  • a drying step such as a granulation and/or lyophilization step and/or spray drying step, to obtain a dried composition (e.g., a solid composition).
  • a drying step such as a granulation and/or lyophilization step and/or spray drying step, to obtain a dried composition (e.g., a solid composition).
  • a drying step such as
  • the dried composition may be obtained as, or subject to further processing to obtain, a powder or granules, or compressed into tablets.
  • the dried composition may be formulated as a dray oral pharmaceutical composition.
  • a dry oral pharmaceutical composition as described herein may be in the form of a powder or granules (optionally packaged in a sachet or stick pack or filled into a capsule), or tablets, for example.
  • the present disclosure also provides uses of the pharmaceutical compositions described herein in treatment methods comprising orally administering an oral pharmaceutical composition as described herein to a subject in need thereof.
  • the subject may be a human subject suffering from prostate cancer, and typically is a male subject although also could be a female subject.
  • the prostate cancer may be advanced prostate cancer, including prostate cancer that does not response to hormone therapy or surgical treatment to lower testosterone, or that has spread to other parts of the body.
  • the composition may be administered at any therapeutically effective dose by any suitable dosing regimen.
  • a pharmaceutical composition described herein that comprises enzalutamide may be administered once daily in an amount that provides a daily dose of enzalutamide of about 160 mg, or less (such as from 50 mg to less than 160 mg, including about 100 mg enzalutamide).
  • a nanoscale size may enhance dissolution rate, and enhance the intrinsic solubility and saturation concentration of the enzalutamide, resulting in increased bioavailability.
  • the use of an enhancer may further improve bioavailability, such as by enhancing intestinal permeation flux and reducing the risk of in situ precipitation.
  • enzalutamide compositions as described herein may exhibit a bioavailability equal to or greater than that of XTANDI®, and/or may require a lower dose for therapeutic efficacy.
  • the enzalutamide compositions described herein may contain the same amount of enzalutamide in a smaller volume than enzalutamide compositions prepared with non-nanosized enzalutamide, and therefore provide the same dose in a smaller volume, offer advantages such as improve convenience and easier administration for the patient.
  • Nanocrystals of enzalutamide were prepared by a process as described above and outlined in FIG. 1, using the following components.
  • the average particle size diameter and polydispersity index (PDI) of the nanocrystals obtained from each formulation were measured by dynamic light scattering. The results are reported in the table below, which shows the impact of the stabilizer on the average particle size.
  • the nanocrystal size distribution profile determined at the time of manufacture is shown in FIG. 2. As seen in the figure, all samples showed a unimodal size distribution, with particles at nanometer scale.
  • Example 1 The physical stability of the enzalutamide nanocrystals obtained in Example 1 was assessed over 42 days at room temperature, with assessments performed at 7, 21, and 42 days. Results are presented in the table below. As seen in the table, only relatively small variations in size and polydispersity index (PDI) were observed (e.g., ⁇ 10% or less).
  • PDI polydispersity index
  • the composition comprising polyvinyl alcohol (4-88) as a low-viscosity polymeric stabilizer showed the greatest stability.
  • Formulations ENC-005 and ENC-006 exhibited essentially the same results and so are plotted on the same curve. Visual inspection of the samples revealed that formulations ENC-001 and ENC-004 showed the lowest sedimentation rate, which is an indication of greater physical stability of these formulations.
  • Nanocrystals were produced using different formulations and process parameters, varying the amount of enzalutamide (from 2 to 15 %), PVA 4-88 (from 2 to 5 %) and polysorbate 80 (from 0 to 2 %), and varying milling time (from 90 to 240 minutes) and milling speed (from 1000 to 2000 RPM).
  • the obtained nanocrystals were analyzed for size and PDI by DLS. Results are set forth below. Some test conditions were excluded for resulting in unacceptably inefficient grinding: enzalutamide concentrations greater than 15%, grinding time less than 90 minutes; speed less than 1000 RPM.
  • Nanocrystals with a size ranging from 169.9 to 320.7 nm and a PDI from 10.4 % to 29.0 % were obtained. From the statistical analysis, it was determined that enzalutamide concentration, milling time, and milling speed have the most significant impact on the average size and PDI of the nanocrystals.

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Abstract

La présente invention concerne des procédés de préparation de nanocristaux d'enzalutamide, des compositions et des compositions pharmaceutiques les contenant, et des méthodes thérapeutiques les utilisant.
PCT/IB2023/062806 2022-12-16 2023-12-15 Nanocristaux d'enzalutamide, méthodes et compositions Ceased WO2024127361A1 (fr)

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